The overall goal of this project is to develop genetically-engineered tumor vaccines for the treatment of human malignant melanoma. We propose to focus on improving the immunogenicity of melanomas by transduction with cytokine genes. Two melanoma vaccine trials will be conduced. A RAC-approved IL-2 trial will use a transduced "universal cell line" mixed with untransduced autologous tumor and clinically test the hypothesis that bystander production of this cytokine will stimulate a tumor-specific immune response. An IRB-submitted IL-7 vaccine trial is based on our extensive basic and preclinical testing of this cytokine. The IL-7 clinical trial will be the first occasion in which this cytokine is tested in humans. Uniform protocol design and immunological end-points will allow a direct comparison of these two cytokines. We will conduct preclinical testing of GM-CSF/IL-3 hybrid gene transduction of experimental tumors and human melanoma. Our preliminary results with IL-3 suggest that this is a superior cytokine in increasing immunogenicity of transduced murine experimental tumors We also plan to develop novel strategies for cytokine-based tumor vaccines using recombinant adenovirus (AdV) vectors. AdV vectors bearing marker and cytokine genes will be tested in ex vivo and in vivo tumor transduction models. In summary, a clinically-oriented Project is proposed to test the ability of cytokine gene therapy to enhance the immunogenicity of human melanoma.